DataSheet1_Assessing the role of lipid-lowering therapy on multi-cancer prevention: A mendelian randomization study.ZIP

Background: Statin use for cancer prevention has raised wide attention but the conclusions are still controversial. Whether statins use have exact causal effects on cancer prevention remains unclear.Methods: Based on the Genome-Wide Association Studies (GWAS) datasets from the large prospective UK Biobank and other consortium databases, two-sample mendelian randomization (MR) analysis was conducted to explore the causal effects of statins use on varied site-specific cancer risks. Five MR methods were applied to investigate the causality. The stability, heterogeneity, and pleiotropy of MR results were also evaluated.Results: The atorvastatin use could increase the risk of colorectal cancer (odd ratio (OR) = 1.041, p = 0.035 by fixed-effects inverse variance weighted (IVW) method (IVWFE), OR = 1.086, p = 0.005 by weighted median; OR = 1.101, p = 0.048 by weighted mode, respectively). According to the weighted median and weighted mode, atorvastatin could modestly decrease the risk of liver cell cancer (OR = 0.989, p = 0.049, and OR = 0.984, p = 0.004, respectively) and head and neck cancer (OR = 0.972, p = 0.020). Besides, rosuvastatin use could reduce the bile duct cancer risk by 5.2% via IVWEF method (OR = 0.948, p = 0.031). No significant causality was determined in simvastatin use and pan-cancers via the IVWFE or multiplicative random-effects IVW (IVWMRE) method if applicable (p > 0.05). There was no horizontal pleiotropy observed in the MR analysis and the leave-one-out analysis proved the stability of the results.Conclusion: The causalities between statin use and cancer risk were only observed in colorectal cancer and bile duct cancer in the European ancestry population. Future works are warranted to provide more robust evidence for supporting statin repurposing for cancer prevention.

背景：他汀类药物在癌症预防中的应用引发了广泛关注，但其结论仍存在争议。他汀类药物的使用是否对癌症预防具有确切的因果效应尚不明确。方法：基于来自大型前瞻性英国生物样本库及其他合作数据库的全基因组关联研究（GWAS）数据集，本研究采用了双样本孟德尔随机化（MR）分析方法，以探讨他汀类药物使用对多种特定癌症风险因果效应的影响。本研究应用了五种MR方法来探究因果关系，并对MR结果的稳定性、异质性和多效性进行了评估。结果：根据固定效应逆方差加权（IVWFE）方法，阿托伐他汀的使用可能会增加结直肠癌的风险（比值比（OR）= 1.041，p = 0.035），而根据加权中位数和加权众数，其风险分别为（OR = 1.086，p = 0.005）和（OR = 1.101，p = 0.048）。根据加权中位数和加权众数，阿托伐他汀的使用可能适度降低肝细胞癌（OR = 0.989，p = 0.049，和OR = 0.984，p = 0.004）和头颈部癌症（OR = 0.972，p = 0.020）的风险。此外，通过逆方差加权效应（IVWEF）方法，罗伐他汀的使用可以降低胆管癌风险5.2%（OR = 0.948，p = 0.031）。在应用逆方差加权效应（IVWFE）或乘法随机效应IVW（IVWMRE）方法的情况下，未在辛伐他汀的使用与全癌症之间确定显著的因果关联（p > 0.05）。在MR分析和留一法分析中未观察到水平多效性，且留一法分析证实了结果的稳定性。结论：仅在具有欧洲血统的人群中，观察到他汀类药物的使用与结直肠癌和胆管癌风险之间的因果关系。未来研究有必要提供更可靠的证据，以支持他汀类药物在癌症预防中的重新应用。